Allopregnanolone relieves paclitaxel induced mechanical hypersensitivity via inhibiting spinal cord PGE2-EP2 mediated microglia-neuron signaling
Chemotherapy-induced neuropathic pain (CINP) is a serious adverse effect of commonly used chemotherapeutics. Neurosteroid allopregnanolone is suggested to modulate the expression of various receptors or enzymes that involved in pain perception, presenting an analgesic potential. Here, we investigate...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
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| Series: | IBRO Neuroscience Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667242125000119 |
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| Summary: | Chemotherapy-induced neuropathic pain (CINP) is a serious adverse effect of commonly used chemotherapeutics. Neurosteroid allopregnanolone is suggested to modulate the expression of various receptors or enzymes that involved in pain perception, presenting an analgesic potential. Here, we investigated if allopregnanolone attenuates extracellular signal-regulated kinase (ERK) and its downstream prostaglandin E2 (PGE2) expression in the dorsal spinal cord concomitant with neuropathic pain relief in paclitaxel (PTX)-induced neuropathic pain model rats. The results showed PTX upregulated phosphorylated ERK (p-ERK), PGE2 level, and PGE2 receptor E-prostanoid 2 (EP2) expression in the spinal dorsal horn. Besides, p-ERK inhibitor PD98059 or microglia inhibitor minocycline reduced microglial activation, p-ERK expression, PGE2 release, EP2 expression, and partially alleviated PTX-induced mechanical hypersensitivity. Further, allopregnanolone level in the dorsal spinal cord was observed to decrease in CINP rats, and intragastric administration of exogenous allopregnanolone dose-dependently alleviated PTX-induced mechanical hypersensitivity. Mechanistically, allopregnanolone dose-dependently alleviated PTX-induced microglial activation, p-ERK, PGE2, and EP2 upregulation, as well as cytokines expression in the dorsal spinal cord in CINP rats. Furthermore, subcutaneous injection of allopregnanolone synthesis inhibitor medroxyprogesterone could reduce endogenous allopregnanolone and block all effects of exogenous allopregnanolone in CINP rats. Taken together, these results suggest allopregnanolone presents an analgesic effect for PTX-induced mechanical hypersensitivity, partially via inhibiting the dorsal spinal cord PGE2-EP2 mediated microglia-neuron signaling. |
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| ISSN: | 2667-2421 |